Breast cancer is a leading cause of cancer death among women. Antiestrogen drugs, such as tamoxifen (Tam), are effective in the treatment of estrogen receptor alpha (ER)- positive breast tumors by slowing the growth of the tumors, preventing the recurrence of the disease, and with relatively few side effects. However, almost all responsive tumors eventually develop of Tarn-resistance. The mechanism(s) responsible for resistance and/or growth promoting effects of Tam are not clear at present. Studies from our group and others indicated estrogen-induced MARK activation (Erk1&2) is predominantly mediated by HRG/HER- 2/PKC-delta/Ras pathway. We have recently shown the following: (a) Three out of four antiestrogen resistant cell lines overexpress total and activated PKC-delta, (b) Overexpression of PKC-delta in Tarn-sensitive MCF- 7 cells leads to Tam-resistance both in vitro and in vivo, (c) Inhibition of PKC-delta by rottlerin or siRNA significantly reversed antiestrogen resistance, (d) Pretreatment of cells with rottlerin followed by TRAIL significantly enhanced apoptosis in antiestrogen resistant cells compared with sensitive cells in vitro, (e) PKC-delta levels are higher in Tarn-resistant tumors compared to Tam-sensitive tumors in MCF-7 tumor xenograft, (f) Immunohistochemical staining of Tarn-resistant human breast tumors showed a significant increase of PKC-delta levels compared with those in Tam-sensitive tumors. Based on the above results, we hypothesize that overexpression and/or activation of PKC-delta plays a major role in the regulation of antiestrogen resistance in ER-positive breast tumor cells. We are proposing the following four specific aims to test our hypotheses: Aim 1. We will determine the molecular mechanism by which PKC-delta overexpression and/or activation suppresses apoptosis in antiestrogen resistant cell lines. Aim 2. We will investigate how PKC-delta and/or its down stream signaling molecules regulate antiestrogen resistance. Aim 3. We will determine mechanism by which PKC-delta inhibitors) sensitizes antiestrogen resistant cells to TRAIL- induced apoptosis. Aim 4. We will develop treatment strategies to translate in vitro observations into practically applicable therapies in vivo. We anticipate that the proposed investigations would reveal novel insights into the mechanism by which PKC-delta regulates antiestrogen-resistance and the data should provide defined molecular target(s) for future clinical intervention for the treatment of breast cancer.